Mark Esser : Excellent! So, thank you for the introduction, Mark [the introducer], and it’s really a pleasure to share with all of you a little bit of the journey that the “long-acting antibody” team has taken in 2020, but actually our story begins back in 2017 in the basement of a Quality Inn in Tysons Corner VA at the Defense Department Industry Day.

There, I met Col. Matt Hepburn, who is actually the architect of the Pandemic Prevention Program or P3, and the goal of P3 was going from the discovering a novel virus to producing drugs in less than 60 days – something that would normally take 6 years at best.

To me that sounded more like science fiction than science, but we signed up in a small and committed team of virologists and molecular biologists and engineers and started working in 2018 on new technologies to discover and manufacture antibodies against viruses. The team has actually been pretty successful on the early discovery engine piece and had won a biopharma R&D award about this time last year.

So, in January we were all anxiously following the emerging news from China about the new disease. It wasn’t a surprise to me when I got a call on February 4th from the Defense Department here in the US saying that the newly discovered SARS-2 virus posed a national security threat. We needed to stop everything we were doing on our model system influenza, and put everything onto SARS-2.

Fortunately, our top 2 virologists, Patrick and ??? were already a step ahead, having cloned and expressed the virus protein soon after the virus sequence was published on January 21st. Of course, the task was formidable: we had to learn everything we could about the new virus, the immune response to the virus, and the disease called “COVID-19”.

What we and others quickly learned was that the critical protein on the virus is called the “spike protein” and this is the protein on the virus that allows the virus to infect cells by binding to the ACE-2 receptor, and what we also learned was that it could exist in active and an inactive form.

In the active form, it expressed a special domain called a Receptor Binding Domain, or the RBD, and what we quickly figured out was that RBD was going to be the “Achilles’ heel” of the virus. So, we decided that our best strategy was to come up with two antibodies against this Receptor Binding Domain, and we set out with a three-pronged approach to discover those antibodies.

First, we tried to isolate these B-cells from the blood taken from Covid-19 patients. Second, we immunized humanized mice with different constructs of spike protein to elicit those magical B-cells, and third, we ran a huge screen using our traditional Cambridge antibody technology phage display library.

All in all, we screened tens of thousands of antibodies, and then discovered about 1500 that bound the spike protein and whittled it down to our top 100 by the end of March. The team worked late into the night, weekends – their commitment was inspiring, and they surprised me with their “top 12” neutralizing antibodies on my birthday, April 10th.

The next challenge was to down-select from these 12 neutralizing antibodies to our “top 2”. The best way I can describe this is like trying to put together a jigsaw puzzle while blindfolded, but at the end the team selected two very distinct, two very potent antibodies that showed synergistic activity. When I say, “synergistic activity”, it was 1% + 1% actually equaled 93% neutralization.

At the same time, our protein engineers, who are in my mind are some of the best in the world, made key enhancements to the antibodies to extend their half-lives so that a single dose could afford up to 6 to 12 months of protection, ensure high yield production in 15,000 liter bioreactors, and be stable up to 1 year in a refrigerator.

So, all in all, all this was done in just 99 days – 1 day ahead of schedule. So, our last hurdle to overcome was to accelerate that normal kind of 2 to 3 year early development timeline into 2 months, and we basically did that by running everything in parallel, and making significant investments at risk. Two notable examples were manufacturing of the Cho-cell pools and starting out tech transfer to our tech transfers to our manufacturing partners before we had even selected our top clones.

Our clinical and regulatory teams worked around the clock, and we dosed our first patient on August 21st [2020], and I am happy to report that we started our two Phase 3 studies: PROVENT last week, and yesterday we dosed first patient in my favorite study, “Storm Chaser” yesterday.

It’s really been astonishing to see how everyone in the company has pulled together and risen to the challenge, and I’ve had the good fortune working with everyone in Biopharma R&D, Precision Medicine, Legal, Business Development, Procurement, Project Management, Ops [Operations], IT [Information Technology], Commercial and the all-important Government Affairs, and I’d like to take this moment to thank everyone.

So, clearly, fighting a virus like SARS-2 in a worldwide pandemic is not for the faint of heart, but clearly, we are all in this fight to the finish. Also, very grateful to Pascal [Soriot, AstraZeneca CEO], Mene (Sir Menelaus Pangalos, an AstraZeneca board member) and Nesset (sp) for their leadership, and I am very proud to be part of the company that not only follow the science but is putting patients first and doing what is right thing for the whole world.

Just like the antibody we are “better together” and I look forward to being with many of you in a healthier and happier 2021. So, thank you and over to you, Pascal.

Pascal Soriot : Thank you, Mark, and congratulations again to you and the team. This long-acting antibodies are quite unique because this is the only combination that potentially will last more than 6 months, up to potentially 12 months and protect people for a long period of time.

And for those of you who may not be totally familiar with antibodies, you know, you have to know a number of people cannot be vaccinated, like if you have an immune disease, lupus or some other immune condition… or multiple sclerosis, you cannot be vaccinated. So, there are millions of people in the world that will need the protection that cannot be coming from a vaccine, so the long-acting antibody has the enormous potential.